Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K.
Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K.
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DOI：
10.1016/j.leukres.2011.04.003
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发表时间：
2011-07
影响因子：
2.7
通讯作者：
Chan RJ
中科院分区：
文献类型：
--
作者：
Yang Z;Chen M;Sitarski SA;Saadatzadeh T;Yin F;Yu M;Yang FC;Chan RJ
激活PTPN 11突变体促进Erk的造血祖细胞过度激活和对GM-CSF的超敏反应。我们假设Ras 1激酶抑制因子（KSR 1）有助于激活PTPN 11诱导的GM-CSF超敏反应。对表达WT Shp 2、Shp 2 E76 K或Shp 2D 61 Y的WT和KSR 1 −/−小鼠的骨髓祖细胞进行功能和生化评价。在表达Shp 2D 61 Y和ShpE 76 K的细胞中，KSR 1活化和与磷酸化Erk的相互作用增强。KSR 1的遗传破坏部分地使Shp 2 E76 K诱导的GM-CSF超敏反应正常化，但未能纠正Shp 2D 61 Y诱导的GM-CSF超敏反应。总的来说，这些研究表明，表达Shp 2 E76 K的细胞比表达Shp 2D 61 Y的细胞对GM-CSF超敏反应的KSR 1的依赖性更大。
Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1−/− mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y.
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